In recent years a strong correlation has been established between high levels of serum cholesterol and atherosclerosis a major form of cardiovascular disease. For this reason a major research effort has been directed toward elucidation of the natural mechanism for regulation of cholesterol biosynthesis and the development of inhibitors of the biosynthetic process to be used when the natural system fails to adequately control cholesterol levels. The key enzyme in the natural regulation system appears to be HMG-CoA reductase which catalyzes the convention of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) to mevalonic acid (MVA) by way of the intermediate mevaldic acid-coenzyme A hemithioacetal. If the biosynthetic steps catalyzed by this key enzyme can be selectively blocked through the use of inhibitors it should be possible to regulate the entire biosynthetic sequence for cholesterol. We have, therefore, proposed the chemical synthesis of five analogs of HMG-CoA and the hemithioacetal intermediate. These analogs closely resemble the natural substrate and intermediate in structure but cannot be enzymatically converted to MVA. Since the inhibitors were designed to closely mimic the natural materials in bonding characteristics they should readily bind to the active site of the enzyme. If the enzyme is then unable to release the inhibitor or does so only slowly it will be effectively prevented from further catalyzing the formation of MVA and the biosynthetic pathway to cholesterol will be blocked. The proposed chemical syntheses will be carried out using modifications of standard modern synthetic methods. Compounds having appropriately protected and substituted structures similar to those of HMG and mevaldic acid but including an analog of the cysteamine group of coenzyme A will be prepared first. The remainder of the proposed structures will then be added using procedures previously developed for the chemical synthesis of coenzyme A itself.